Design and rationale of a multi-center, pragmatic, open-label randomized trial of antimicrobial therapy - the study of clinical efficacy of antimicrobial therapy strategy using pragmatic design in Idiopathic Pulmonary Fibrosis (CleanUP-IPF) clinical trial

Compelling data have linked disease progression in patients with idiopathic pulmonary fibrosis (IPF) with lung dysbiosis and the resulting dysregulated local and systemic immune response. Moreover, prior therapeutic trials have suggested improved outcomes in these patients treated with either sulfamethoxazole/ trimethoprim or doxycycline. These trials have been limited by methodological concerns. This trial addresses the primary hypothesis that long-term treatment with antimicrobial therapy increases the time-to-event endpoint of respiratory hospitalization or all-cause mortality compared to usual care treatment in patients with IPF. We invoke numerous innovative features to achieve this goal, including: 1) utilizing a pragmatic randomized trial design; 2) collecting targeted biological samples to allow future exploration of 'personalized' therapy; and 3) developing a strong partnership between the NHLBI, a broad range of investigators, industry, and philanthropic organizations. The trial will randomize approximately 500 individuals in a 1:1 ratio to either antimicrobial therapy or usual care. The site principal investigator will declare their preferred initial antimicrobial treatment strategy (trimethoprim 160 mg/ sulfamethoxazole 800 mg twice a day plus folic acid 5 mg daily or doxycycline 100 mg once daily if body weight is < 50 kg or 100 mg twice daily if ≥50 kg) for the participant prior to randomization. Participants randomized to antimicrobial therapy will receive a voucher to help cover the additional prescription drug costs. Additionally, those participants will have 4-5 scheduled blood draws over the initial 24 months of therapy for safety monitoring. Blood sampling for DNA sequencing and genome wide transcriptomics will be collected before therapy. Blood sampling for transcriptomics and oral and fecal swabs for determination of the microbiome communities will be collected before and after study completion. As a pragmatic study, participants in both treatment arms will have limited in-person visits with the enrolling clinical center. Visits are limited to assessments of lung function and other clinical parameters at time points prior to randomization and at months 12, 24, and 36. All participants will be followed until the study completion for the assessment of clinical endpoints related to hospitalization and mortality events. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT02759120

Biphasic investigation of contact mechanics in natural human hips during activities

The aim of this study was to determine the cartilage contact mechanics and the associated fluid pressurisation of the hip joint under eight daily activities, using a three-dimensional finite element hip model with biphasic cartilage layers and generic geometries. Loads with spatial and temporal variations were applied over time and the time-dependent performance of the hip cartilage during walking was also evaluated. It was found that the fluid support ratio was over 90% during the majority of the cycles for all the eight activities. A reduced fluid support ratio was observed for the time at which the contact region slid towards the interior edge of the acetabular cartilage, but these occurred when the absolute level of the peak contact stress was minimal. Over 10 cycles of gait, the peak contact stress and peak fluid pressure remained constant, but a faster process of fluid exudation was observed for the interior edge region of the acetabular cartilage. The results demonstrate the excellent function of the hip cartilage within which the solid matrix is prevented from high levels of stress during activities owing to the load shared by fluid pressurisation. The findings are important in gaining a better understanding of the hip function during daily activities, as well as the pathology of hip degeneration and potential for future interventions. They provide a basis for future subject-specific biphasic investigations of hip performance during activities

ER and HER2 expression are positively correlated in HER2 non-overexpressing breast cancer

PMCID: PMC3446380This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited

A miRNA-Target Prediction Case Study

Giansanti, V., Castelli, M., Beretta, S., & Merelli, I. (2019). Comparing Deep and Machine Learning Approaches in Bioinformatics: A miRNA-Target Prediction Case Study. In V. V. Krzhizhanovskaya, M. H. Lees, P. M. A. Sloot, J. J. Dongarra, J. M. F. Rodrigues, P. J. S. Cardoso, J. Monteiro, ... R. Lam (Eds.), Computational Science – ICCS 2019: 19th International Conference, Faro, Portugal, June 12–14, 2019, Proceedings, Part III (pp. 31-44). (Lecture Notes in Computer Science (including subseries Lecture Notes in Artificial Intelligence and Lecture Notes in Bioinformatics); Vol. 11538 LNCS). Springer Verlag. https://doi.org/10.1007/978-3-030-22744-9_3MicroRNAs (miRNAs) are small non-coding RNAs with a key role in the post-transcriptional gene expression regularization, thanks to their ability to link with the target mRNA through the complementary base pairing mechanism. Given their role, it is important to identify their targets and, to this purpose, different tools were proposed to solve this problem. However, their results can be very different, so the community is now moving toward the deployment of integration tools, which should be able to perform better than the single ones. As Machine and Deep Learning algorithms are now in their popular years, we developed different classifiers from both areas to verify their ability to recognize possible miRNA-mRNA interactions and evaluated their performance, showing the potentialities and the limits that those algorithms have in this field. Here, we apply two deep learning classifiers and three different machine learning models to two different miRNA-mRNA datasets, of predictions from 3 different tools: TargetScan, miRanda, and RNAhybrid. Although an experimental validation of the results is needed to better confirm the predictions, deep learning techniques achieved the best performance when the evaluation scores are taken into account.authorsversionpublishe

Inter-rater reliability of categorical versus continuous scoring of fish vitality: does it affect the utility of the reflex action mortality predictor (RAMP) approach?

Scoring reflex responsiveness and injury of aquatic organisms has gained popularity as predictors of discard survival. Given this method relies upon the individual interpretation of scoring criteria, an evaluation of its robustness is done here to test whether protocol-instructed, multiple raters with diverse backgrounds (research scientist, technician, and student) are able to produce similar or the same reflex and injury score for one of the same flatfish (European plaice, Pleuronectes platessa) after experiencing commercial fishing stressors. Inter-rater reliability for three raters was assessed by using a 3-point categorical scale (‘absent’, ‘weak’, ‘strong’) and a tagged visual analogue continuous scale (tVAS, a 10 cm bar split in three labelled sections: 0 for ‘absent’, ‘weak’, ‘moderate’, and ‘strong’) for six reflex responses, and a 4-point scale for four injury types. Plaice (n = 304) were sampled from 17 research beam-trawl deployments during four trips. Fleiss kappa (categorical scores) and intra-class correlation coefficients (ICC, continuous scores) indicated variable inter-rater agreement by reflex type (ranging between 0.55 and 0.88, and 67% and 91% for Fleiss kappa and ICC, respectively), with least agreement among raters on extent of injury (Fleiss kappa between 0.08 and 0.27). Despite differences among raters, which did not significantly influence the relationship between impairment and predicted survival, combining categorical reflex and injury scores always produced a close relationship of such vitality indices and observed delayed mortality. The use of the continuous scale did not improve fit of these models compared with using the reflex impairment index based on categorical scores. Given these findings, we recommend using a 3-point categorical over a continuous scale. We also determined that training rather than experience of raters minimised inter-rater differences. Our results suggest that cost-efficient reflex impairment and injury scoring may be considered a robust technique to evaluate lethal stress and damage of this flatfish species on-board commercial beam-trawl vessels

High Quality Genomic Copy Number Data from Archival Formalin-Fixed Paraffin-Embedded Leiomyosarcoma: Optimisation of Universal Linkage System Labelling

Most soft tissue sarcomas are characterized by genetic instability and frequent genomic copy number aberrations that are not subtype-specific. Oligonucleotide microarray-based Comparative Genomic Hybridisation (array CGH) is an important technique used to map genome-wide copy number aberrations, but the traditional requirement for high-quality DNA typically obtained from fresh tissue has limited its use in sarcomas. Although large archives of Formalin-fixed Paraffin-embedded (FFPE) tumour samples are available for research, the degradative effects of formalin on DNA from these tissues has made labelling and analysis by array CGH technically challenging. The Universal Linkage System (ULS) may be used for a one-step chemical labelling of such degraded DNA. We have optimised the ULS labelling protocol to perform aCGH on archived FFPE leiomyosarcoma tissues using the 180k Agilent platform. Preservation age of samples ranged from a few months to seventeen years and the DNA showed a wide range of degradation (when visualised on agarose gels). Consistently high DNA labelling efficiency and low microarray probe-to-probe variation (as measured by the derivative log ratio spread) was seen. Comparison of paired fresh and FFPE samples from identical tumours showed good correlation of CNAs detected. Furthermore, the ability to macro-dissect FFPE samples permitted the detection of CNAs that were masked in fresh tissue. Aberrations were visually confirmed using Fluorescence in situ Hybridisation. These results suggest that archival FFPE tissue, with its relative abundance and attendant clinical data may be used for effective mapping for genomic copy number aberrations in such rare tumours as leiomyosarcoma and potentially unravel clues to tumour origins, progression and ultimately, targeted treatment

Temozolomide followed by combined immunotherapy with GM-CSF, low-dose IL2 and IFNα in patients with metastatic melanoma

The purpose of this study is to determine the toxicity and efficacy of temozolomide (TMZ) p.o. followed by subcutaneous (s.c.) low-dose interleukin-2 (IL2), granulocyte-monocyte colony stimulating factor (GM-CSF) and interferon-alpha 2b (IFN alpha) in patients with metastatic melanoma. A total of 74 evaluable patients received, in four separate cohorts, escalating doses of TMZ (150-250 mg m(-2)) for 5 days followed by s.c. IL2 (4 MIU m(-2)), GM-CSF (2.5 microg kg(-1)) and IFN alpha (5 MIU flat) for 12 days. A second identical treatment was scheduled on day 22 and cycles were repeated in stable or responding patients following evaluation. Data were analysed after a median follow-up of 20 months (12-30 months). The overall objective response rate was 31% (23 out of 74; confidence limits 20.8-42.9%) with 5% CR. Responses occurred in all disease sites including the central nervous system (CNS). Of the 36 patients with responding or stable disease, none developed CNS metastasis as the first or concurrent site of progressive disease. Median survival was 252 days (8.3 months), 1 year survival 41%. Thrombocytopenia was the primary toxicity of TMZ and was dose- and patient-dependent. Lymphocytopenia (grade 3-4 CTC) occurred in 48.5% (34 out of 70) fully monitored patients following TMZ and was present after immunotherapy in two patients. The main toxicity of combined immunotherapy was the flu-like syndrome (grade 3) and transient liver function disturbances (grade 2 in 20, grade 3 in 15 patients). TMZ p.o. followed by s.c. combined immunotherapy demonstrates efficacy in patients with stage IV melanoma and is associated with toxicity that is manageable on an outpatient basi

Dietary supplement increases plasma norepinephrine, lipolysis, and metabolic rate in resistance trained men

Correction to Richard J Bloomer, Kelsey H Fisher-Wellman, Kelley G Hammond, Brian K Schilling, Adrianna A Weber and Bradford J Cole: Dietary supplement increases plasma norepinephrine, lipolysis, and metabolic rate in resistance trained men. Journal of the International Society of Sports Nutrition 2009, 6: